rs767984672

Variant names:

• chr19-50261508-C-A
• rs767984672
• NM_001145809.2:c.2458C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50261508-C-A
• chr19-50261508-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_Moderate BS1_Supporting

The NM_001145809.2(MYH14):​c.2458C>A​(p.Arg820Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000386 in 1,554,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R820C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000024 (0 hom., cov: 17)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.88
• Publications: 0 publications found

Genes affected

MYH14 (HGNC:23212): (myosin heavy chain 14) This gene encodes a member of the myosin superfamily. The protein represents a conventional non-muscle myosin; it should not be confused with the unconventional myosin-14 (MYO14). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene result in one form of autosomal dominant hearing impairment. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

MYH14 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 4A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000024 (3/124918) while in subpopulation AMR AF = 0.000252 (3/11910). AF 95% confidence interval is 0.0000685. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 17. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	NM_001145809.2	MANE Select	c.2458C>A	p.Arg820Ser	missense	Exon 21 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.2359C>A	p.Arg787Ser	missense	Exon 20 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.2335C>A	p.Arg779Ser	missense	Exon 19 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.2458C>A	p.Arg820Ser	missense	Exon 21 of 43	ENSP00000493594.1
	MYH14	ENST00000599920.5	TSL:1	c.2359C>A	p.Arg787Ser	missense	Exon 20 of 24	ENSP00000469573.1
	MYH14	ENST00000425460.6	TSL:5	c.2359C>A	p.Arg787Ser	missense	Exon 20 of 42	ENSP00000407879.1

Frequencies

GnomAD3 genomes AF: 0.0000240 AC: 3 AN: 124918 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000252

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000872 AC: 2 AN: 229392 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000187

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1429336 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 710120

African (AFR) AF: 0.00 AC: 0 AN: 31534

American (AMR) AF: 0.0000241 AC: 1 AN: 41452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.00 AC: 0 AN: 36034

South Asian (SAS) AF: 0.00 AC: 0 AN: 81222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097184

Other (OTH) AF: 0.0000169 AC: 1 AN: 59150

GnomAD4 genome AF: 0.0000240 AC: 3 AN: 124918 Hom.: 0 Cov.: 17 AF XY: 0.0000336 AC XY: 2 AN XY: 59606

African (AFR) AF: 0.00 AC: 0 AN: 31338

American (AMR) AF: 0.000252 AC: 3 AN: 11910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3126

East Asian (EAS) AF: 0.00 AC: 0 AN: 4242

South Asian (SAS) AF: 0.00 AC: 0 AN: 3318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59856

Other (OTH) AF: 0.00 AC: 0 AN: 1620

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.064	T
Polyphen		0.99	D
Vest4		0.85
MutPred		0.63		Gain of methylation at K784 (P = 0.0453)
MVP		0.87
MPC		1.4
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.76
gMVP		0.90
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs767984672; hg19: chr19-50764765;